rs244656

Positions:

• chr5-134114136-T-A
• chr5-134114136-T-C
• chr5-134114136-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001401008.1(VDAC1):​c.-709A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 152,076 control chromosomes in the GnomAD database, including 45,223 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (45223 hom., cov: 32)
• Consequence: VDAC1 NM_001401008.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63

Genes affected

TCF7 (HGNC:11639): (transcription factor 7) This gene encodes a member of the T-cell factor/lymphoid enhancer-binding factor family of high mobility group (HMG) box transcriptional activators. This gene is expressed predominantly in T-cells and plays a critical role in natural killer cell and innate lymphoid cell development. The encoded protein forms a complex with beta-catenin and activates transcription through a Wnt/beta-catenin signaling pathway. Mice with a knockout of this gene are viable and fertile, but display a block in T-lymphocyte differentiation. Alternative splicing results in multiple transcript variants. Naturally-occurring isoforms lacking the N-terminal beta-catenin interaction domain may act as dominant negative regulators of Wnt signaling. [provided by RefSeq, Oct 2016]

VDAC1 (HGNC:12669): (voltage dependent anion channel 1) This gene encodes a voltage-dependent anion channel protein that is a major component of the outer mitochondrial membrane. The encoded protein facilitates the exchange of metabolites and ions across the outer mitochondrial membrane and may regulate mitochondrial functions. This protein also forms channels in the plasma membrane and may be involved in transmembrane electron transport. Alternate splicing results in multiple transcript variants. Multiple pseudogenes of this gene are found on chromosomes 1, 2 3, 6, 9, 12, X and Y.[provided by RefSeq, Sep 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7	XM_047417635.1	c.26T>A	p.Val9Asp	missense_variant	1/10		XP_047273591.1
TCF7	XM_047417634.1	c.26T>A	p.Val9Asp	missense_variant	1/11		XP_047273590.1
TCF7	XM_047417636.1	c.26T>A	p.Val9Asp	missense_variant	1/12		XP_047273592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115711 AN: 151958 Hom.: 45216 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.770

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.761 AC: 115760 AN: 152076 Hom.: 45223 Cov.: 32 AF XY: 0.756 AC XY: 56209 AN XY: 74328

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.853

Gnomad4 SAS AF: 0.744

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.863

Gnomad4 OTH AF: 0.769

Alfa AF: 0.805 Hom.: 6221

Bravo AF: 0.752

Asia WGS AF: 0.770 AC: 2678 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.5
DANN	Benign	0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs244656; hg19: chr5-133449827;